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PKC-Theta-Mediated Signal Delivery from Thetcr/CD28 Surface Receptors

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PKC-Theta-Mediated Signal Delivery from Thetcr/CD28 Surface Receptors REVIEW ARTICLE published: 22 August 2012 doi: 10.3389/fimmu.2012.00273 PKC-theta-mediated signal delivery from theTCR/CD28 surface receptors Noah Isakov1* and Amnon Altman2 1 The Shraga Segal Department of Microbiology and Immunology, Faculty of Health Sciences and the Cancer Research Center, Ben-Gurion University of the Negev, Beer Sheva, Israel 2 Division of Cell Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA, USA Edited by: Protein kinase C-theta (PKCθ) is a key enzyme inT lymphocytes, where it plays an important Nick Gascoigne, Scripps Research role in signal transduction downstream of the activated T cell antigen receptor (TCR) and Institute, USA the CD28 costimulatory receptor. Interest in PKCθ as a potential drug target has increased Reviewed by: following recent findings that PKCθ is essential for harmful inflammatory responses medi- Balbino Alarcon, Consejo Superior de Investigaciones Cientificas, Spain ated byTh2 (allergies) andTh17 (autoimmunity) cells as well as for graft-versus-host disease Salvatore Valitutti, INSERM, France (GvHD) and allograft rejection, but is dispensable for beneficial responses such as antiviral *Correspondence: immunity and graft-versus-leukemia (GvL) response. TCR/CD28 engagement triggers the Noah Isakov, The Shraga Segal translocation of the cytosolic PKCθ to the plasma membrane (PM), where it localizes at Department of Microbiology and the center of the immunological synapse (IS), which forms at the contact site between an Immunology, Faculty of Health Sciences and the Cancer Research antigen-specificT cell and antigen-presenting cells (APC). However, the molecular basis for Center, Ben-Gurion University this unique localization, and whether it is required for its proper function have remained of the Negev, P.O. Box 653, unresolved issues until recently. Our recent study resolved these questions by demon- Beer Sheva 84105, Israel. θ e-mail: [email protected] strating that the unique V3 (hinge) domain of PKC and, more specifically, a proline-rich motif within this domain, is essential and sufficient for its localization at the IS, where it is anchored to the cytoplasmic tail of CD28 via an indirect mechanism involving Lck protein tyrosine kinase (PTK) as an intermediate. Importantly, the association of PKCθ with CD28 is essential not only for IS localization, but also for PKCθ-mediated activation of downstream signaling pathways, including the transcription factors NF-κB and NF-AT,which are essential for productive T cell activation. Hence, interference with formation of the PKCθ-Lck-CD28 complex provides a promising basis for the design of novel, clinically useful allosteric PKCθ inhibitors. An additional recent study demonstrated that TCR triggering activates the ger- minal center kinase (GSK)-like kinase (GLK) and induces its association with the SLP-76 adaptor at the IS, where GLK phosphorylates the activation loop of PKCθ, converting it into an active enzyme. This recent progress, coupled with the need to study the biology of PKCθ in human T cells, is likely to facilitate the development of PKCθ-based therapeutic modalities for T cell-mediated diseases. Keywords: protein kinase C-theta, PKCθ, CD28, Lck, signal transduction, costimulation INTRODUCTION process and describes in more detail the studies that clarified a new Protein kinase C-theta (PKCθ) is a key regulator of signal trans- mechanism by which PKCθ is being recruited to the center of the duction in activated T cells that is linked to multiple pathways IS and is essential for the induction of PKCθ-dependent activation downstream of the T cell antigen receptor (TCR; Isakov and signals. Altman, 2002). Engagement of the TCR and the resulting forma- tion of diacylglycerol (DAG) are sufficient for promoting PKCθ THE PKC FAMILY recruitment to cell membranes (Monks et al., 1997, 1998). How- Protein kinase C was discovered by Nishizuka and colleagues, who ever, localization of PKCθ to the immunological synapse (IS) is demonstrated a new kinase that undergoes activation by lim- entirely dependent on the concomitant ligation of the CD28 core- ited proteolysis (Inoue et al., 1977), or by translocation to the ceptor (Huang et al., 2002). Localization of PKCθ at the center plasma membrane (PM), where it associates with specific cofac- of the IS is essential for activation of signaling pathways that tors (Takai et al., 1979). The membrane-associated PKC-activating promote T cell-dependent immune responses against distinct anti- factor turned to be DAG (Kishimoto et al., 1980). DAG, together gens and pathogens. While the recruitment of PKCθ to the IS of with inositol 1,4,5-trisphophate (IP3), are products of phospho- TCR/CD28 engaged T cells has been extensively studied, informa- lipase C-mediated hydrolysis of the membrane phospholipid, tion on the molecular basis for this highly selective process has phosphatidylinositol 4,5-bisphosphate (PIP2; Berridge and Irvine, been relatively scarce until recently. The present manuscript pro- 1984; Nishizuka, 1984). These two second messengers transduce vides background information on the molecules involved in this signals from a plethora of activated receptors: the hydrophobic www.frontiersin.org August 2012 | Volume 3 | Article 273 | 1 “fimmu-03-00273” — 2012/8/21 — 17:51 — page1—#1 Isakov and Altman TCR/CD28-linked PKCθ-mediated signaling DAG remains bound to the cell membrane where, in addition to events leading to activation of transcription factors, including PKC, it activates effector molecules such as RasGRP, a guanine NF-κB, AP-1, and NF-AT, which are critical for T cell activa- nucleotide exchange factor (GEF) for Ras (Lorenzo et al., 2000), tion, proliferation and differentiation (Baier-Bitterlich et al., 1996; while the hydrophilic IP3 diffuses through the cytosol and binds Coudronniere et al., 2000; Dienz et al., 2000; Lin et al., 2000; 2+ IP3-receptors, which function as ligand-gated Ca channels in Sun et al., 2000; Pfeifhofer et al., 2003). Under certain activa- the endoplasmic reticulum (ER), thereby triggering the release of tion conditions, PKCθ can translocate to the nucleus where it free Ca2+ ions into the cytoplasm (Takai et al., 1979; Khan et al., directly associates with chromatin and is involved in the regu- 1992; Bourguignon et al., 1994). The utilization of phorbol esters, lation of microRNAs and T cell-specific inducible gene expression which mimic the activity of DAG, together with Ca2+ ionophores, program (Sutcliffe et al., 2011). The exact mechanism by which demonstrated that PKC also plays an essential role in the induc- the membrane-bound PKCθ delivers signals to the nucleus has tion of T lymphocyte proliferation (Truneh et al., 1985; Isakov and not been fully resolved but studies provided information on a Altman, 1987) and reactivation of effector cytotoxic T cells (Isakov number of effector molecules that operate along this pathway and Altman, 1985; Isakov et al., 1987). in activated T cells. These studies demonstrated that PKCθ- Protein kinase C enzymes transduce a myriad of signals from mediated regulation of NF-κB activity involves the multisubunit a large number of cell surface receptors that are coupled to inhibitor of κB(IκB) kinase (IKK) complex (Coudronniere et al., phospholipase C and phospholipid hydrolysis. They regulate the 2000; Dienz et al., 2000; Khoshnan et al., 2000; Lin et al., 2000; function of effector molecules by phosphorylating specific serine Bauer et al., 2001). and threonine residues. The PKC family includes 10 structurally An important upstream effector in the NF-κB signaling path- and functionally related isoforms (for more details, see the first wayisIκBα, which binds NF-κB in the cytoplasm of resting T cells review by Pfeifhofer-Obermair et al., 2012), grouped into three and mask its nuclear localization signal (NLS), thereby preventing subfamilies based on the composition of their regulatory domains NF-κB translocation to the nucleus (Mercurio et al., 1997; Regnier and their respective cofactor requirements (Newton, 1995; Mel- et al., 1997; Jacobs and Harrison, 1998). IKK-mediated phospho- lor and Parker, 1998). The first subfamily includes conventional rylation of IκBα signals the protein for degradation (Karin, 1999), PKCs (cPKC; α, βI, βII, γ) that are regulated via two DAG-binding exposes the NF-κB NLS and promotes NF-κB translocation to C1 domains organized in tandem near the cPKC amino termi- the nucleus and the induction of NF-κB-mediated gene transcrip- nus (Hurley et al., 1997; Johnson et al., 2000; Ho et al., 2001) tion.TcellsfromPKCθ-deficient (Prkcq−/−) mice fail to respond and an adjacent Ca2+ and phospholipid-binding C2 domain to TCR stimulation with degradation of IκBα (Sun et al., 2000), (Nalefski and Falke, 1996; Johnson et al., 2000). The second supporting the model whereby PKCθ regulates NF-κB activity group includes novel PKCs (nPKC; δ, ε, η, θ) that are DAG- through its effect on IKK-IκBα. Some of the effector molecules dependent, but Ca2+ and phospholipid independent for their that link PKCθ to IKK have been identified and include the PKCθ activity. The third group includes atypical PKCs (aPKC: ζ, λ/ι) substrate protein, caspase activation and recruitment domain that are DAG-, Ca2+-, and phospholipid-independent. While (CARD) and membrane-associated guanylate kinase (MAGUK) PKC enzymes are involved in metabolic processes in different domain-containing protein-1 (CARMA1). This scaffold protein cell types, many studies implicate PKC enzymes in signal trans- is primarily expressed in lymphocytes (Bertin et
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